REPURPOSING OF FDA APPROVED COMPOUNDS TO INHIBIT OSM/OSMR SIGNALING IN GLIOBLASTOMA

Repurposing of FDA approved compounds to inhibit OSM/OSMR signaling in glioblastoma OSM/OSMR signalling is important in glioblastoma, yet specific inhibitors to suppress this signaling pathway remain to be explored. Here we conducted HTS screening of FDA approved compounds to identify lead compounds that can suppress OSM signalling via OSMR to inhibit STAT3 phosphorylation. The strategy of drug repurposing that have already been approved by FDA, with known pharmacological and safety profiles, offers several advantages including bypassing development costs and rapid and effective translation into phase 2 clinical trials. Importantly, 99% of newly developed drugs fail in clinical trials, further highlighting the significance of drug repurposing. Our HTS screen revealed 456 compounds with > 40% potency. We analyzed the compounds based on their mode of action and physicochemical properties. Our HTS discovered 63 G-protein coupled receptor modulators including 5-Hydroxy tryptamine (5-HT) and Dopamine receptor D2 (DRD2) modulators as OSM/OSMR inhibitors. Following a counter-screen we focused on compounds with highest potency as well as their potential to cross BBB using physicochemical attributes and the safety profiles previously established in human patients. These analyses revealed 7 lead compounds which are presently being tested in vivo in combination with present standards of care of glioblastoma patients.